title: Structural and thermodynamic effects of post-translational modifications in mutant and wild type Cu, Zn superoxide dismutase.
abstract: Aggregation of Cu,Zn superoxide dismutase (SOD1) is implicated in amyotrophic lateral sclerosis. Glutathionylation and phosphorylation of SOD1 is omnipresent in the human body, even in healthy individuals, and has been shown to increase SOD1 dimer dissociation, which is the first step on the pathway toward SOD1 aggregation. We found that post-translational modification of SOD1, especially glutathionylation, promotes dimer dissociation. We discovered an intermediate state in the pathway to dissociation, a conformational change that involves a "loosening" of the β-barrels and a loss or shift of dimer interface interactions. In modified SOD1, this intermediate state is stabilized as compared to unmodified SOD1. The presence of post-translational modifications could explain the environmental factors involved in the speed of disease progression. Because post-translational modifications such as glutathionylation are often induced by oxidative stress, post-translational modification of SOD1 could be a factor in the occurrence of sporadic cases of amyotrophic lateral sclerosis, which represent 90% of all cases of the disease.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Proctor
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D050505:Mutant Proteins; D013482:Superoxide Dismutase